Researchers at UCLA's Drug Discovery Lab and Department of Chemistry have developed new chemical entity (NCE) analogs of A03, which together form a new class of compounds that target apolipoprotein E4 (ApoE4)-mediated deficits in the tau deacetylase enzyme, sirtuin 1 (SirT1). These NCEs provide an opportunity for novel therapeutic development in Alzheimer's Disease and could be effective in other CNS disorders.
BACKGROUND:
Alzheimer's disease (AD) is an increasingly prevalent progressive neurodegenerative disorder characterized by the presence of plaques and neurofibrillary tangles in brain tissue that ultimately cause impairment in cognition, learning, and memory recall. The neurodegeneration continues to progress until essential life functions are impossible, causing the patient to be disabled. As of 2021, about 6 million Americans are living with AD. This number is projected to increase to over 10 million by 2050. Additional AD and other dementias are estimated to cost the US ~$350 billion annually, and by 2050 these costs could triple in amount. As population models expect the median age in developed nations to increase, there is an increasing need and financial incentive for developing AD treatments that effectively ameliorate the disease. Current FDA-approved drug mechanisms for targeting AD focus on increasing acetylcholine activity, but this only helps delay cognitive decline. The recently approved drug Aducunamab has modest effects on cognition. There is an urgent need for the development of novel pharmaceuticals that can effectively treat AD.
INNOVATION:
UCLA researchers have previously reported A03, a compound for treating AD by reducing AD-associated symptoms and disease progression. Formerly, independent reports have indicated that ApoE4-mediated reduction in sirtuin 1 (SirT1) levels is significant in AD. After screening for compounds that lead to increases in SirT1 through interactions of ApoE4 associated pathways and the discovery of A03 that increases SirT1 while not affecting SirT2 levels, UCLA researchers in the Drug Discovery Lab have focused on the characterization of the mechanism of action of A03 in addition to creating novel analogs with similar activity. Through these efforts, they have synthesized a new family of compounds and NCE's which show promise for treating AD and CNS disorders. Alternatively, this family of compounds could serve as an effective scaffold for future therapeutic optimization throught a novel mechanism targeting ApoE4. Compounds have been selected for their capacity following evaluation in vitro. Testing in vivo with mouse AD models is currently ongoing.
POTENTIAL APPLICATIONS:
• Treatment of AD at various stages
• Treatment of other CNS disorders
• Brain stimulant
• Pre-emptive treatment for the maintenance of healthy memory and cognition
ADVANTAGES:
• The compound family contains analogs with varying molecular weights and IC 50s
• Compounds show similar activity as reported A03
• The relative variance provide various starting points as scaffolds for further optimization
DEVELOPMENT-TO-DATE: A03 has previously been reported in the literature to increase SirT1 levels in the hippocampus of an industry-standard Alzheimer's disease (AD) mouse model and, through this, elicited cognitive improvement while inducing no observed toxicity. These NCEs have been tested in vitro and have been selected for similar binding activity. Testing in vivo for these compounds is currently ongoing.
Related Papers:
Campagna, Jesus et al. "A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer's disease mouse model." Scientific reports vol. 8,1 17574. 4 Dec. 2018, doi:10.1038/s41598-018-35687-8